Trophic support and myelination of axons by Schwann cells in the peripheral nervous system (PNS) are essential for normal nerve function. Disruptions to myelin result in many neurological diseases, including Charcot-Marie-Tooth disease and numerous other peripheral neuropathies. Aberrant Schwann cell physiology leads to axon degeneration, demonstrating that glial-derived signals are required for axonal integrity. Non- myelinating Schwann cells in peripheral nerves, known as Remak Schwann cells, surround and ensheath small diameter axons into ?Remak bundles,? and structural defects in Remak bundles were shown to be associated with chronic pain. Schwann cell?axonal interactions are thus essential for proper nerve function, but the extent to which neurons contribute to Remak Schwann cell development is not well understood. In a mouse model of tuberous sclerosis, in which cortical neurons lack Tuberous sclerosis 1 (Tsc1), a negative regulator of the master regulator of protein synthesis, mTOR (mammalian Target Of Rapamycin), a striking delay in myelination was observed. Furthermore, loss of Tsc2, another negative regulator of mTOR, in excitatory neurons affects astrocyte development. These studies indicate that mTOR activation by neuronal deletion of Tsc1 or Tsc2 affects the development of glia, including oligodendrocytes and astrocytes. In agreement with these studies, our preliminary results in the peripheral nervous system indicate that in mice lacking Tsc2 in sensory neurons, Remak bundles are disorganized: the Remak bundles are oddly shaped and possess abnormally large diameter axons as well as fewer axons per bundle. We also noted thicker myelin around some axons and evidence of lost axon-Schwann cell contact. These results indicate that Tsc2 deletion and the resulting activation of mTOR in sensory neurons generates abnormal signals that disrupt Schwann cell development and/or maintenance, with a prominent effect on Remak bundles. Our goal is to understand the molecular mechanisms by which neuronal mTOR signaling impacts Schwann cells and Remak bundle organization. In Aim 1 we will expand and thoroughly define the consequence of Tsc2 deletion in sensory neurons on Schwann cell development and peripheral nerve function. In Aim 2, we will use genetic and next generation sequencing approaches to identify the molecular mechanisms underlying neuronally induced Schwann cell defects. These studies will help elucidate the role of axonally-derived signals in Remak Schwann cell development and may uncover new therapeutic avenues to treat peripheral neuropathy.